Strains of influenza A (H3N2) virus have specific mutations in the M2 proton channel that result in resistance to the antiviral drug amantadine, one of the very few drugs currently available against the virus. Recent years have witnessed a dramatic increase in resistance to amantadine in communities in Asia and North America due to the spread of the H3N2 strain despite the absence of sustained selective drug pressure. Another important problem that limits the use of amantadine is its interference with the human NMDA receptor, causing potentially severe side effects. For these reasons, we propose to use NMR- and fragment-based screening approaches to derive novel agents against H3N2 influenza A infections by directly targeting the mutant M2 variants. In addition, we propose to target an essential RNA viral promoter by using similar NMR- based approaches. The chemical structures, SAR data and range of biochemical activities of the resulting compounds will provide a framework onto which to develop potentially novel anti-influenza therapies. [unreadable] [unreadable] [unreadable]